Introduction
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in older adults, distinguished by neurofibrillary tangles (NFTs) and neurotic plaques formed as a result of the accumulation of amyloid-beta (Aβ) peptides, most commonly in the neocortical structures and medial temporal lobe of the brain. Advanced age is the single most significant risk factor for AD. Symptoms generally appear after the age of 60 for unexplained reasons. This condition affects around one out of every eight adults aged 65 to 74. A person’s genetic makeup may also raise their chances of developing AD. People who have one or two copies of the APOE-e4 gene, for example, are more likely to develop the condition. The Alzheimer’s disease continuum defines the course of AD from undetectable brain alterations to brain changes that cause memory issues and finally physical incapacity. The three stages are preclinical Alzheimer’s disease, Alzheimer’s-related moderate cognitive impairment (MCI), and Alzheimer’s-related dementia. Variable but substantial alterations and mild-to-moderate impairments in numerous cognitive, functional, and behavioural domains are seen in people with very mild or mild AD dementia.
Changes in mood, sleep, and anxiety are some of the first signs that appear years before a clinical diagnosis of dementia. In the preclinical or early phases of AD, anxiety, depressive symptoms, apathy, and withdrawal are common. Progression to later-stage symptoms like impaired judgment, disorientation, confusion, severe behavioural changes like aggression and agitation, and neuropsychiatric symptoms like delusions and hallucinations can go unnoticed and undertreated until diagnosis. Considering the disease’s increasing prevalence and mortality, the pressure to discover effective procedures for the early identification of AD is immense. Even though no effective medications can reverse existing pathological alterations, delaying disease progression by lowering the risks and early interventions will conserve the patient’s functional level for a long time. With the realization that immediate action is needed to decrease the burden of AD, a disease with rapidly rising expenses and few treatment choices, the focus has shifted to specifying people far earlier in the disease process. Even though there is presently no treatment or cure for dementia, it is vital to raise detection rates so that those who are most at risk can be found early and steps can be taken to reduce or stop the disease’s progression. Receiving an early diagnosis has several advantages for the patient, including providing a reason for the symptoms and signs they are experiencing and ending their suspicions.
Review
This section mainly focuses on imaging techniques that help in the early diagnosis of AD. In the clinical setting, structural neuroimaging is often used to distinguish between different kinds of dementia. Computed tomography (CT) and magnetic resonance imaging (MRI) can be used to visualize and evaluate structural changes in the brain, giving a measure of cerebral atrophy. MRI and CT were the first imaging techniques utilized for Alzheimer’s disease. Still, they were employed to rule out other causes of dementia rather than to identify AD at an early stage. Although CT is the most commonly utilized due to its inexpensive cost and ubiquitous availability, MRI provides superior contrast and tissue characterization.
Structural MRI (sMRI)
Protons have rotational momentum polarized in a magnetic field, which is exploited in MRI. This means that a radiofrequency pulse can change the energy state of protons. After the pulse is shut off, the protons will release a radiofrequency signal as they return to their original energy level. Combining several gradients and pulses can create “sequences” that are sensitive to varied tissue features. Post-mortem examinations have indicated that the medial temporal lobe structures, especially the entorhinal cortex, and hippocampus, are the first to change in AD. This pattern aids in diagnosing disease by imaging the above-mentioned brain areas. Studies show a close relationship between hippocampal volume loss and AD. Hence the volumetric measure of the hippocampus helps determine the early stages of AD.
With roughly 80% accuracy, sMRI alone can predict later conversion to AD in MCI cases. In imaging, hippocampus volumetry is the most well-established structural biomarker for AD, especially for early diagnosis. Also, as it does not use ionizing radiation, MRI is considered safe and non-invasive. One of the critical advantages of MRI is the availability of equipment in hospitals and research facilities. However, the molecular specificity of sMRI is low. It can’t see the histological hallmarks of AD that include Aβ proteins and NFTs. As a result, one of the most substantial limitations of sMRI is the inability to directly detect the effects of Aβ plaques or NFTs in the brain. sMRI demands specialized expertise and can result in high levels of measurement variability. The volume of the hippocampus or medial temporal lobe, has low sensitivity and specificity, disqualifying sMRI as a stand-alone add-on test for AD dementia early detection.
Functional MRI (fMRI)
The bold oxygen level-dependent (BOLD) signal, which detects blood flow and volume change, is used in fMRI to construct dynamic representations of brain activity. fMRI can be used to examine the functional connectivity within specific brain networks during cognitive tasks, typically comparing one condition to a control condition. It can also explore the functional connectivity within a particular brain network during the resting state. The intrinsic oscillations or time course of the BOLD signal between the brain regions are examined using functional connectivity MRI (fc-MRI) techniques.
Visuospatial ability, working memory, attention, semantic understanding, and motor performance are areas where fMRI findings in AD have been discovered. Although fMRI provides unique insight into pathophysiology, it is not recommended for routine clinical usage .The BOLD fMRI response varies between people, and there have been few investigations on the repeatability of fMRI activation in older and cognitively challenged people reported so far. Longitudinal fMRI investigations in individuals with progressive dementias are challenging for various reasons. Because these approaches are compassionate to head motion, fMRI is likely to be challenging to use in investigating individuals with more severe cognitive impairment. One of the critical benefits of task fMRI activation investigations is lost if the patients cannot complete the cognitive task correctly. In more seriously handicapped individuals, resting-state fMRI could be more possible.
Positron emission tomography (PET)
PET is a useful technique for examining human brain activity in vivo. It can measure brain metabolism, receptor binding for numerous neurotransmitter systems, and changes in regional blood flow without being intrusive. PET radioligands bind to a receptor, transporter, or enzyme. This technique could be valuable for diagnosing neurological disorders, devising treatments, and monitoring disease development. The brain runs almost entirely on glucose as an energy source. Fluorodeoxyglucose (FDG), a glucose analogue, is a good indicator of brain metabolism and can be detected with PET when labelled with fluorine-18. FDG-PET is mainly based on the hypometabolism of regions which in turn suggests neurodegeneration. Therefore, stages of AD before neuronal degeneration are not detected. Aβ plaques and NFTs deposition occur before neurodegeneration initiation, and FDG-PET fails to detect these depositions.
Tau-PET
There has been no effective reversal or reduction of AD symptoms by targeting AB. As a result, the focus of AD therapy research has switched to the function of tau in AD pathogenesis. Tau is a protein abundantly expressed in CNS associated with neurons microtubules and helps stabilize the microtubules of axons. Tau proteins form insoluble fibers called paired helical filaments (PHFs) after hyperphosphorylation in AD, which later form aggregates in the cytoplasm of neurons leading to the formation of NFTs.
Additionally, they must exhibit high specificity and rapid clearance rate. The ultrastructural PHF types of tau aggregates are most prevalent in AD. Hence most attempts to produce tau-PET tracers have focused on imaging these PHFs. A few of the tracers used in tau-PET are pyrido−indole derivatives, quinoline derivatives, PBB3, and 18F-FDDNP.
Conclusion
Alzheimer’s mainly impacts older adults causing dementia due to neurodegeneration. AD is a disorder with a long duration of subclinical stages. The role of imaging techniques for early diagnosis is largely utilized in prevention studies. This article discussed imaging modalities commonly used to diagnose AD, their advantages, and their limitations. However, advanced MRI techniques like arterial spin labeling and diffuse tensor imaging (DTI) are also pitched to understand AD. In PET imaging, efforts to develop suitable ligands with high selectivity and affinity are ongoing. Therefore, no single imaging technique is adequate for early diagnosis, which led to a new concept called “multi-modal imaging”. In this method, to increase diagnostic accuracy, the same patient is subjected to numerous techniques. By this, the strengths and weaknesses of different techniques complement each other increasing the diagnostic value.
Among the techniques mentioned above, PET imaging is obviously to be relatively more helpful in early diagnosis. But in a practical world, all suspected cases cannot be subjected to PET imaging. The clinical significance of this article is to accentuate the fact that no radio diagnostic method is conclusive on its own and multi-modal imaging helps narrow down the cases in definite need of advanced molecular imaging, therefore avoiding suspected cases from going through unnecessary imaging. Further studies should be carried out to develop more sophisticated techniques and discover better, safe, accessible, and cost-effective biomarkers to increase the current probability to diagnose AD early.